use of tumor markers in testicular, prostate, colorectal, breast, and ...

Chapter 6
Tumor Markers in Ovarian Cancer
Daniel W. Chan, Robert C. Bast Jr, Ie-Ming Shih, Lori J. Sokoll, and György Sölétormos
BACKGROUND
In the United States, ovarian cancer is among the top four most
lethal malignant diseases in women, who have a lifetime probability
of developing the disease of 1 in 59 (397). Worldwide,
the incidence of ovarian cancer was estimated in as 204,499
cases per year with corresponding 124,860 deaths (398).
The overall mortality of ovarian cancer is still poor despite
new chemotherapeutic agents, which have significantly improved
the 5-year survival rate (118). The main reason is lack of success
in diagnosing ovarian cancer at an early stage, as the great majority
of patients with advanced stage of ovarian carcinoma die of
the disease. In contrast, if ovarian cancer is detected early, 90%
of those with well-differentiated disease confined to the ovary
survive. Furthermore, biomarkers that can reliably predict clinical
behavior and response to treatment are generally lacking. The
search for tumor markers for the early detection and outcome
prediction of ovarian carcinoma is therefore of profound importance
and represents one of the critical subjects in the study of
ovarian cancer.
Although ovarian cancer is often considered to be a single
disease, it is composed of several related but distinct tumor categories
including surface epithelial tumors, sex-cord stromal
tumors, germ cell tumors (399). Within each category, there are
several histological subtypes. Of these, epithelial tumors (carcinomas)
are the most common and are divided, according to
Federation of Gynecology and Obstetrics (FIGO) and WHO
classifications, into five histologic types: serous, mucinous,
endometrioid, clear cell, and transitional (400). The different
types of ovarian cancers are not only histologically distinct but
are characterized by different clinical behavior, tumorigenesis,
and pattern of gene expression. Based on prevalence and mortality,
the serous carcinoma is the most important, representing the
majority of all primary ovarian carcinomas with a dismal clinical
outcome (401). Therefore, unless otherwise specified, serous
carcinoma is what is generally thought of as ovarian cancer.
The search for more effective biomarkers depends on a better
understanding of the pathogenesis of ovarian cancer (ie, the
molecular events in its development). Based on a review of
recent clinicopathological and molecular studies, a model for the
development of ovarian carcinomas has been proposed (402). In
this model, surface epithelial tumors are divided into two broad
categories designated type I and type II tumors which correspond
to two main pathways of tumorigenesis. Type I tumors
tend to be low-grade neoplasms that arise in a stepwise fashion
51
from borderline tumors whereas type II tumors are high-grade
neoplasms for which morphologically recognizable precursor
lesions have not been identified, so-called “de novo” development.
As serous tumors are the most common surface epithelial
tumors, low-grade serous carcinoma is the prototypic type I
tumor and high-grade serous carcinoma is the prototypic type
II tumor. In addition to low-grade serous carcinomas, type I
tumors are composed of mucinous carcinomas, endometrioid
carcinomas, malignant Brenner tumors, and clear cell carcinomas.
Type I tumors are associated with distinct molecular
changes that are rarely found in type II tumors, such as BRAF
and KRAS mutations for serous tumors, KRAS mutations for
mucinous tumors, and -catenin, PTEN mutations, and MSI for
endometrioid tumors. Type II tumors include high-grade serous
carcinoma, malignant mixed mesodermal tumors (carcinosarcoma),
and undifferentiated carcinoma. There are very limited
data on the molecular alterations associated with type II tumors,
except frequent p53 mutations in high-grade serous carcinomas
and malignant mixed mesodermal tumors (carcinosarcomas).
This model of carcinogenesis provides a molecular platform for
the discovery of new ovarian cancer markers.
In order to prepare these guidelines, the literature relevant
to the use of tumor markers in breast cancer was reviewed.
Particular attention was given to reviews including systematic
reviews, prospective randomized trials that included the use of
markers, and guidelines issued by expert panels. Where possible,
the consensus recommendations of the NACB panel were
based on available evidence (ie, were evidence based).
CURRENTLY AVAILABLE MARKERS
FOR OVARIAN CANCER
The most widely studied ovarian cancer body fluid- and tissue-based
tumor markers are listed in Table 15, which also
summarizes the phase of development of each marker and the
LOE for its clinical use. The LOE grading system is based on
a previous report describing the framework to evaluate clinical
utility of tumor markers (120). The following discussion
focused mainly on CA125, which is the only marker that has
been accepted for clinical use in ovarian cancer. The NACB
panel does not recommend clinical utilization of other biomarkers
in diagnosis, detection, or monitoring of ovarian cancer
as all other markers are either in the evaluation phase or in
the research/discovery phase.